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The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation

Oncogene volume 24, pages 7599–7607 (2005)Cite this article

Abstract

c-Src associates with and is activated by the ErbB-2 receptor tyrosine kinase, but is unable to bind the EGFR. Although c-Src has been found to interact directly and specifically with the ErbB-2 receptor, the significance of this interaction is unclear. Using both chimeric receptor and site-directed mutagenesis approaches, the region of interaction of c-Src on ErbB-2 was identified. Significantly, EGFR could be converted into a receptor capable of binding c-Src by replacement of a catalytic domain of ErbB-2. We further demonstrated that MDCK cells that express mutant EGFR that are competent in c-Src recruitment lose epithelial polarity in organoid cultures, whereas cells overexpressing the wild-type EGFR retain a polarized phenotype. ErbB-2-dependent activation of c-Src results in disruption of epithelial cell–cell contacts leading to cell dispersal that correlates with the re-localization of phospho-MAPK to focal adhesions. Taken together, these observations suggest that recruitment of c-Src to these closely related EGFR family members plays a critical role in modulating cell polarity.

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Acknowledgements

This work was supported by grants from the US Army (DAMD) and CBCRA awarded to WJM. A CBCRA grant was awarded to MP. HK was supported by a studentship from the CIHR, and RC was supported by a Pre-doctoral scholarship from the US Army (DAMD). WJM is a recipient of a CRC chair in Molecular Oncology. MP is a CIHR senior scientist.

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Authors and Affiliations

  1. Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada

    Harold Kim

  2. Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, M4N 3M5, Ontario, Canada

    Harold Kim

  3. Department of Biology, McMaster University, Hamilton, Ontario, Canada

    Richard Chan & David L Dankort

  4. Department of Biochemistry, Molecular Oncology Group, McGill University, Montreal, H3A 1A1, Quebec, Canada

    Richard Chan, Dongmei Zuo, Monica Najoukas, Morag Park & William J Muller

  5. Department of Medicine, Molecular Oncology Group, McGill University, Montreal, H3A 1A1, Quebec, Canada

    Richard Chan, Dongmei Zuo, Monica Najoukas, Morag Park & William J Muller

  6. UCSF Comprehensive Cancer Center, UCSF Cancer Research Institute, San Francisco, 94115, CA, USA

    David L Dankort

  7. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    William J Muller

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Correspondence to William J Muller.

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Kim, H., Chan, R., Dankort, D. et al. The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation. Oncogene 24, 7599–7607 (2005). https://doi.org/10.1038/sj.onc.1208898

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